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- PDB-6zoq: Oestrogen receptor ligand binding domain in complex with compound 16 -

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Basic information

Entry
Database: PDB / ID: 6zoq
TitleOestrogen receptor ligand binding domain in complex with compound 16
ComponentsEstrogen receptor
KeywordsGENE REGULATION / oestrogen receptor
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation / epithelial cell development / vagina development / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone receptor signaling pathway / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / 14-3-3 protein binding / protein localization to chromatin / estrogen receptor signaling pathway / steroid binding / nitric-oxide synthase regulator activity / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ESR-mediated signaling / transcription corepressor binding / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / nuclear receptor activity / Regulation of RUNX2 expression and activity / positive regulation of fibroblast proliferation / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / regulation of inflammatory response / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / fibroblast proliferation / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / calmodulin binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / : / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / : / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type
Similarity search - Domain/homology
Chem-QNE / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBreed, J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.
Authors: Scott, J.S. / Moss, T.A. / Balazs, A. / Barlaam, B. / Breed, J. / Carbajo, R.J. / Chiarparin, E. / Davey, P.R.J. / Delpuech, O. / Fawell, S. / Fisher, D.I. / Gagrica, S. / Gangl, E.T. / ...Authors: Scott, J.S. / Moss, T.A. / Balazs, A. / Barlaam, B. / Breed, J. / Carbajo, R.J. / Chiarparin, E. / Davey, P.R.J. / Delpuech, O. / Fawell, S. / Fisher, D.I. / Gagrica, S. / Gangl, E.T. / Grebe, T. / Greenwood, R.D. / Hande, S. / Hatoum-Mokdad, H. / Herlihy, K. / Hughes, S. / Hunt, T.A. / Huynh, H. / Janbon, S.L.M. / Johnson, T. / Kavanagh, S. / Klinowska, T. / Lawson, M. / Lister, A.S. / Marden, S. / McGinnity, D.F. / Morrow, C.J. / Nissink, J.W.M. / O'Donovan, D.H. / Peng, B. / Polanski, R. / Stead, D.S. / Stokes, S. / Thakur, K. / Throner, S.R. / Tucker, M.J. / Varnes, J. / Wang, H. / Wilson, D.M. / Wu, D. / Wu, Y. / Yang, B. / Yang, W.
History
DepositionJul 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,3024
Polymers57,3112
Non-polymers9912
Water1,60389
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-14 kcal/mol
Surface area20020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.350, 51.630, 85.450
Angle α, β, γ (deg.)90.000, 93.250, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-725-

HOH

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Components

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 28655.521 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Chemical ChemComp-QNE / ~{N}-[4-[(6~{S},8~{R})-7-[(1-fluoranylcyclopropyl)methyl]-8-methyl-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-3-methoxy-phenyl]-1-(3-fluoranylpropyl)azetidin-3-amine


Mass: 495.607 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H35F2N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.04 Å3/Da / Density % sol: 39.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350, magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jan 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.8→40.37 Å / Num. obs: 41885 / % possible obs: 97.6 % / Redundancy: 3.2 % / Biso Wilson estimate: 35.38 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.024 / Rpim(I) all: 0.015 / Rrim(I) all: 0.029 / Net I/σ(I): 22.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.8-1.852.20.241593926860.9050.1950.312385.2
8.06-40.363.20.01315734890.9990.0080.0165092

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6suo

6suo


Resolution: 1.8→40.37 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.136 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.132 / SU Rfree Blow DPI: 0.121 / SU Rfree Cruickshank DPI: 0.124
RfactorNum. reflection% reflectionSelection details
Rfree0.232 2148 5.13 %RANDOM
Rwork0.204 ---
obs0.205 41885 97.4 %-
Displacement parametersBiso max: 122.78 Å2 / Biso mean: 42.61 Å2 / Biso min: 20.19 Å2
Baniso -1Baniso -2Baniso -3
1-4.4195 Å20 Å2-2.6993 Å2
2---4.3104 Å20 Å2
3----0.1091 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 1.8→40.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3511 0 72 89 3672
Biso mean--38.2 40.88 -
Num. residues----459
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1264SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes595HARMONIC5
X-RAY DIFFRACTIONt_it3667HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion482SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4373SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3667HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4981HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion16.36
LS refinement shellResolution: 1.8→1.82 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2848 31 3.7 %
Rwork0.2187 807 -
all0.2212 838 -
obs--80.31 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.603-0.6335-0.92621.55580.37571.7729-0.0417-0.3367-0.0318-0.03030.0525-0.00930.03510.4738-0.0108-0.1330.07720.00140.07860.018-0.110319.9578-5.715723.3482
22.91130.2457-0.48460.6518-0.02252.6550.0458-0.0187-0.0131-0.01430.10010.0522-0.2488-0.2434-0.1459-0.10630.06750.0205-0.11190.0087-0.0884-3.79325.816622.0708
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A303 - 552
2X-RAY DIFFRACTION2{ B|* }B306 - 547

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